Effect of CD14 Blockade on Endotoxin-Induced Acute Lung Injury in Mice

Tasaka, Sadatomo; Ishizaka, Akitoshi; Yamada, Wakako; Shimizu, Mie; Koh, Hidefumi; Hasegawa, Naoki; Adachi, Yoshiyuki; Yamaguchi, Kazuhiro

doi:10.1165/rcmb.2002-0132oc

Cited by 45 publications

(34 citation statements)

References 34 publications

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“…This amino acid substitution may disrupt IRAK4 signaling and result in a less-effective immune response to invading pathogens so that critically ill patients carrying the C/T/A clade have an increased risk of positive bacterial cultures. Our finding that the C/T/A haplotype clade of IRAK4 is associated with increased prevalence of positive bacterial cultures at admission to the ICU is consistent with our previous studies [36] , and with recent animal studies [37][38][39] which suggest that polymorphisms of innate immunity genes could be associated with impaired clearance of bacteria. A number of studies have shown that rare germline mutations in IRAK4 cause recurring bacterial infections in children and deficiencies in cytokine production in response to a range of microbial-derived TLR agonists and to recombinant IL-1 ␤ or IL-18 [10-13, 40, 41] .…”

Section: Discussionsupporting

confidence: 92%

A Nonsynonymous Polymorphism of IRAK4 Associated with Increased Prevalence of Gram-Positive Infection and Decreased Response to Toll-Like Receptor Ligands

et al. 2011

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Mutations in IRAK4 have been associated with recurrent Gram-positive infections in children. Given the central role of IRAK4 in innate immunity signaling, we hypothesized that common genetic variants of IRAK4 may be associated with prevalence of Gram-positive infection in critically ill adults. Haplotype clade tag single nucleotide polymorphisms (SNPs) of the IRAK4 gene were selected and genotyped in a cohort of 1,029 critically ill patients with systemic inflammatory response syndrome (SIRS). We found that a haplotype clade tagged by the A allele of the htSNP G29429A (Ala428Thr) was associated with increased relative risk of Gram-positive infection at admission to ICU (RR = 1.2, p < 0.05). Furthermore, the 29429A allele was associated with decreased lymphoblastoid cell response to CpG (as measured by IL-6 production) (raw values ± 95% CI 40.3 ± 32.3 vs. 85.8 ± 29.4 pg/ml; log-transformed values ± 95% CI 1.13 ± 0.37 vs. 1.55 ± 0.18, p < 0.04). We also found that IRAK4-deficient fibroblasts transfected with an IRAK4 expression plasmid containing the 29429A allele produced less IL-6 in response to lipopolysaccharide (p = 0.07). Our data suggest that the IRAK4 haplotype clade marked by 29429A (428Thr) alters susceptibility to Gram-positive bacteria, by decreasing cellular response to TLR ligands.

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Section: Discussionsupporting

confidence: 92%

A Nonsynonymous Polymorphism of IRAK4 Associated with Increased Prevalence of Gram-Positive Infection and Decreased Response to Toll-Like Receptor Ligands

et al. 2011

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“…Intratracheal LPS induced lung injury with clear alveolar inflammation, characterized by intra-alveolar neutrophil infiltration and increased lavage fluid proinflammatory cytokines (TNF and MIP-2). There was also an increase in protein concentration in lavage fluid, indicating increased pulmonary endothelial and epithelial permeability, consistent with previous studies (6,30). Intravenous LPS induced lung injury of a predominantly vascular nature.…”

Section: Discussionsupporting

confidence: 91%

Effects of inhaled carbon monoxide on acute lung injury in mice

Ghosh¹,

Wilson²,

Choudhury³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of morbidity and mortality in the intensive care unit, but despite continuing research few effective therapies have been identified. In recent years, inhaled carbon monoxide (CO) has been reported to have cytoprotective effects in several animal models of tissue injury. We therefore evaluated the effects of inhaled CO in three different in vivo mouse models of ALI. Anesthetized C57BL/6 mice were ventilated with oxygen in the presence or absence of CO (500 parts per million) for 1 h before lung injury was induced by lipopolysaccharide (LPS) or oleic acid (OA) administration. Ventilation was then continued with the same gases for a further 2-3 h, with hemodynamic and respiratory parameters monitored throughout. Intratracheal LPS administration induced lung injury with alveolar inflammation (increased lavage fluid neutrophils, total protein, and cytokines). In contrast, intravenous LPS induced a predominantly vascular lung injury, with increased plasma TNF and increased neutrophil activation (surface Mac-1 upregulation and L-selectin shedding) and sequestration within the pulmonary vasculature. Intravenous OA produced deteriorations in lung function, reflected by changes in respiratory mechanics and blood gases and lavage fluid neutrophil accumulation. However, addition of CO to the inspired gas did not produce significant changes in the measured physiological or immunological parameters in the mouse models used in this study. Thus the results do not support the hypothesis that use of inhaled CO is beneficial in the treatment of ALI and ARDS. cytokines; lipopolysaccharide; oleic acid; neutrophil recruitment; pulmonary inflammation ACUTE LUNG INJURY (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are major causes of mortality and morbidity in the intensive care unit. These syndromes are characterized by the development of hypoxemia, alveolar-capillary barrier damage, and pulmonary inflammation, occurring within hours to days of a predisposing insult, which may be of either pulmonary (e.g., pneumonia, aspiration of gut contents) or extrapulmonary (sepsis, acute pancreatitis) nature (32). Despite intense research, few studies have identified therapies that show a beneficial impact on the outcome of ALI, with the exception of the use of lung protective ventilatory strategies (1, 2).Carbon monoxide (CO) has long been known in biology and medicine as a toxic compound, due to its ability to bind hemoglobin with a much higher affinity than oxygen (25). Despite this image as a deadly gas, recent evidence indicates that CO may in fact have a cytoprotective function at low doses. CO is endogenously produced during heme metabolism by the enzyme heme oxygenase, which is one of the major antioxidant cytoprotective enzymes within the body (17,22). Several investigators have reported that exogenously administered CO by inhalation may exert anti-inflammatory effects, providing protection in various animal models of tiss...

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“…Perhaps the most prominent of these is the induction of both innate immune response and stress-related genes. These loci include the CD14 gene, which encodes the receptor for the complex of bacterial lipopolysaccharide (LPS) and LPS-binding protein, and has been recently and previously shown to be essential for the innate immune response to bacterial infection (53). The product of this gene has also been recently shown to mediate the innate immune response to gram-positive bacteria by binding to cell wallderived peptidoglycan-polysaccharide complexes, and this may explain its induction in response to B. anthracis (35).…”

Section: Resultsmentioning

confidence: 99%

Murine Macrophage Transcriptional Responses to Bacillus anthracis Infection and Intoxication

Bergman

Passalacqua

Gaspard³

et al. 2005

Infect Immun

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Interactions between Bacillus anthracis and host macrophages represent critical early events in anthrax pathogenesis, but their details are not clearly understood. Here we report the first genomewide characterization of the transcriptional changes within macrophages infected with B. anthracis and the identification of several hundred host genes that were differentially expressed during this intracellular stage of infection. These loci included both genes that are known to be regulated differentially in response to many other bacterial pathogens and those that appear to be differentially regulated in response to B. anthracis but not other bacterial species that have been tested. These data provide a transcriptional basis for a variety of physiological changes observed during infection, including the induction of apoptosis caused by the infecting bacteria. The expression patterns underlying B. anthracis-induced apoptosis led us to test further the importance of one very highly induced macrophage gene, that for ornithine decarboxylase. Our data show that this enzyme plays an important and previously unrecognized role in suppressing apoptosis in B. anthracis-infected cells. We have also characterized the transcriptional response to anthrax lethal toxin in activated macrophages and found that, following toxin treatment, many of the host inflammatory response pathways are dampened. These data provide insights into B. anthracis pathogenesis as well as potential leads for the development of new diagnostic and therapeutic options.

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Effect of CD14 Blockade on Endotoxin-Induced Acute Lung Injury in Mice

Cited by 45 publications

References 34 publications

A Nonsynonymous Polymorphism of IRAK4 Associated with Increased Prevalence of Gram-Positive Infection and Decreased Response to Toll-Like Receptor Ligands

A Nonsynonymous Polymorphism of IRAK4 Associated with Increased Prevalence of Gram-Positive Infection and Decreased Response to Toll-Like Receptor Ligands

Effects of inhaled carbon monoxide on acute lung injury in mice

Murine Macrophage Transcriptional Responses to Bacillus anthracis Infection and Intoxication

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